Tau-dependent suppression of adult neurogenesis in the stressed hippocampus.

Stress, a well-known sculptor of brain plasticity, is shown to suppress hippocampal neurogenesis in the adult brain; yet, the underlying cellular mechanisms are poorly investigated. Previous studies have shown that chronic stress triggers hyperphosphorylation and accumulation of the cytoskeletal protein Tau, a process that may impair the cytoskeleton-regulating role(s) of this protein with impact on neuronal function. Here, we analyzed the role of Tau on stress-driven suppression of neurogenesis in the adult dentate gyrus (DG) using animals lacking Tau (Tau-knockout; Tau-KO) and wild-type (WT) littermates. Unlike WTs, Tau-KO animals exposed to chronic stress did not exhibit reduction in DG proliferating cells, neuroblasts and newborn neurons; however, newborn astrocytes were similarly decreased in both Tau-KO and WT mice. In addition, chronic stress reduced phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/glycogen synthase kinase-3ß (GSK3ß)/ß-catenin signaling, known to regulate cell survival and proliferation, in the DG of WT, but not Tau-KO, animals. These data establish Tau as a critical regulator of the cellular cascades underlying stress deficits on hippocampal neurogenesis in the adult brain.

Expression and activity of NOD1 and NOD2/RIPK2 signalling in mononuclear cells from patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study was to analyse the expression and function of nucleotide-binding oligomerization domain (NOD)1 and NOD2 in isolated cells of patients with rheumatoid arthritis (RA). METHOD: mRNA expression levels of NOD1, NOD2, and receptor-interacting serine/threonine kinase 2 (RIPK2) genes were determined by quantitative polymerase chain reaction (qPCR) in peripheral blood mononuclear cells (PBMCs) and synovial fluid T cells (SFTCs) isolated from RA and osteoarthritis (OA) patients. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA) in plasma and cell culture supernatants. The stimulatory effect of RA SF was assessed by an in-vitro NOD2 activation assay using nuclear factor kappa B (NF-κB) luciferase-transfected cells. RESULTS: A significantly higher level of NOD2 and RIPK2 mRNA expression, but not NOD1, was observed on PBMCs and SFTCs isolated from RA patients compared to the OA control group. In addition, the NOD2 pathway up-regulation was functional, as stimulation of PBMCs with muramyl dipeptide (MDP) induced the production of higher amounts of tumour necrosis factor (TNF)-α, interleukin (IL)-8, and IL-1ß compared with OA PBMCs. Incubation of PBMCs from healthy donors with recombinant TNF-α or RA serum induced the expression of NOD2 mRNA. Finally, SF isolated from RA patients is able to activate the NF-κB signalling pathway in HEK293T-transfected cells in a NOD2-dependent manner. CONCLUSIONS: Our findings suggest that NOD2/RIPK2 signalling is up-regulated in immune cells of RA patients. Moreover, it seems that there is a NOD2 agonist in the SF of RA patients. Therefore, NOD2/RIPK2 activation can modulate the innate immune response and may play a role in the perpetuation of the inflammatory response in RA.

IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2.

BACKGROUND AND PURPOSE: IL-33 signals through ST2 receptors and induces adaptive and innate inflammation. IL-33/ST2 is involved in adaptive inflammation-induced pain. Here, we have investigated the contribution of IL-33/ST2-triggered mechanisms to carrageenin-induced innate inflammation. EXPERIMENTAL APPROACH: Carrageenin- and IL-33-induced inflammatory responses were assessed in BALB/c- (WT) and ST2-deficient ((-/-) ) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF-α (infliximab), CXCL1 (antibody to CXCL1), IL-1 (IL-1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin). KEY RESULTS: Carrageenin injection increased ST2 and IL-33 mRNA expression and IL-33 production in paw skin samples. Carrageenin-induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2(-/-) compared with WT mice, effects mimicked by IL-33 injection in the paw. Furthermore, IL-33-induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL-33-induced hyperalgesia in naïve mice was reduced by treatments targeting TNF, CXCL1, IL-1, endothelin receptors and COX while carrageenin-induced ST2-dependent TNF-α, CXCL1, IL-1ß, IL-10 and PGE2 production and preproET-1 mRNA expression. Combining IL-33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2-dependent manner. CONCLUSIONS AND IMPLICATIONS: IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL-33/ST2 signalling as a target in innate inflammation and inflammatory pain.

Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis.

OBJECTIVE: To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved. METHODS: RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1ß, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. RESULTS: In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1ß, and TNFα, and showed a diminished expression of GRPR. CONCLUSION: These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.

Xilanase e beta-glucanase na digestibilidade aparente de nutrientes do triticale pela Tilápia-do-nilo / Xylanase and beta-glucanase on nutrient aparent digestibility of triticale by Nile tilapia

Avaliou-se o efeito de diferentes níveis do composto enzimático Natugrain Blend L®, que contém endo-xilanase e endo-beta-glucanase, sobre a digestibilidade dos nutrientes e a energia do triticale pela tilápia-do-nilo. O método para a determinação da digestibilidade foi o indireto, utilizando-se o óxido de crômio III (0,10 por cento). O delineamento experimental foi inteiramente ao acaso, com cinco tratamentos e três repetições. O nível de substituição da dieta-referência foi 50,0 por cento pelo triticale. Os tratamentos foram 0,0; 150,0; 300,0; 450,0 e 600,0mg kg-1 de Natugrain Blend L, que contém 800 unidades g-1 de endo-1,3(4)-β-glucanase (BGU) e 36.600 unidades g-1 de endo-1,4-β-xylanase (EXU). Os coeficientes de digestibilidade aparente foram: da matéria seca, 76,42; 74,01; 83,39; 82,97 e 78,34 por cento; da proteína bruta 88,19; 88,39; 90,52; 92,05 e 88,34 por cento, da energia bruta 75,93; 71,31; 81,78; 80,27 e 78,62 por cento, respectivamente, para os níveis de inclusão na dieta 0,0; 150,0; 300,0; 450,0 e 600,0mg kg-1 de Natugrain Blend L.Os resultados demonstram que 300mg kg-1 do complexo de enzimas foi suficiente para aumentar o coeficiente de digestibilidade aparente da matéria seca. O composto de enzimas pode ser utilizado para aumentar a eficiência de aproveitamento dos nutrientes do triticale.

The effects of different levels of Natugrain Blend L® enzymatic compound on triticale nutrients and energy digestibility by Nile tilapia were evaluated. The digestibility was indirectly determined with chromic oxide III (0.10 percent) as an external marker. The level of substitution by triticale in the reference diet was 50 percent. The treatments were 0, 150, 300, 450, and 600g kg of Natugrain Blend L, which contains 800 units g-1 of endo-1,3(4)-β-glucanase (BGU) and 36.600 units g-1 of endo-1,4-β-xylanase (EXU). The apparent digestibility coefficients were: dry matter 76.42, 74.01, 83.39, 82.97, and 78.34 percent; crude protein 88.19, 88.39, 90.52, 92.05, and 88.34 percent; crude energy 75.93, 71.31, 81.78, 80.27, and 78.62 percent, respectively to inclusion levels of 0.0, 150.0, 300.0, 450.0, and 600.0mg kg-1 of Natugrain Blend L in diet. Results demonstrated that 300mg kg-1 of enzymes were enough to increase the dry matter apparent digestibility coefficient and energy. The enzyme compound can be used to increase the efficiency of triticale feed utilization.

Dissociation of the morphological correlates of stress-induced anxiety and fear.

Chronic stress is a powerful modulator of emotional behaviour. Previous studies have shown that distinct neuronal pathways modulate different emotional behaviours: while the amygdala plays a key role in fear-conditioned-to-cue stimuli, the bed nucleus of stria terminalis (BNST) is implicated in anxiety behaviour and responses to contextual stimuli. In addition, the BNST is directly involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. In the present study, we assessed anxiety (measured in the elevated-plus maze and acoustic startle apparatus) and fear-conditioned responses to light stimuli in rats that had been exposed to either chronic unpredictable stress or corticosterone for 28 days; thereafter, stereological estimates of the BNST and amygdaloid complex were performed, followed by three-dimensional morphometric dendritic analysis. Results show that chronic stress induces hyperanxiety without influencing fear conditioning or locomotion and exploratory activity. Stress-induced hyperanxiety was correlated with increased volumes of the BNST but not of the amygdala. Dendritic remodelling was found to make a significant contribution to the stress-induced increase in BNST volume, primarily due to changes in the anteromedial area of the BNST, an area strongly implicated in emotional behaviour and in the neuroendocrine control of the stress response. Importantly, all of the effects of stress were recapitulated by exogenous corticosterone. In conclusion, this study shows that chronic stress impacts on BNST structure and function; its findings pertain to the modulation of emotional behaviour and the maladaptive response to stress.

Tratamento da luxacao anterior recidivante do ombro pela tecnica de Magnuson-Stack - avaliacao de resultados. / Treatment of anterior recurrent dislocation of the shoulder by the Magnusson-Stack technic - results evaluation

Os autores apresentam o resultado de duas series de pacientes operados pela tecnica de Magnuson-Stack. A 1a. com 24 anos de evolucao (apenas 3 casos), e a 2a., 14 pacientes com 4 anos. Os resultados mostraram ser iguais em ambas, que aliados a simplicidade da operacao e a satisfacao dos pacientes operados,faz-nos indicar esta tecnica em pacientes portadores de Luxacao Anterior Recidivante de Ombro

Lesoes traumaticas raquimedulares agudas Conceitos atuais. / Acute traumatic spinal medullary injuries.Current concepts

O tratamento das lesoes agudas da coluna vertebral e medula espinhal requerem efetivo atendimento medico de emergencia no local do acidente por uma equipe multi-disciplinar de medicos e profissionais para-medicos, coordenados com um hospital-base. Igual atencao deve ser dada tanto pela equipe do pessoal ligado ao sistema nervoso, como pelo pessoal da coluna vertebral

Uma nova opcao nas amputacoes ao nivel do retro-pe. (Tecnica de Revenko) / A new alternative in mid tarsal amputations. (Revenko's technic)

Com o presente trabalho, tencionamos oferecer mais uma opcao tecnica para as amputacoes no retro-pe. O objetivo da tecnica que descrevemos e a preservacao da articulacao do tornozelo, atraves de uma osteotomia e artrodese entre o talus e o calcaneo, e a execucao de um coto eficiente, coberto com a pele da regiao plantar, oferecendo ao paciente uma marcha excelente sem a necessidade de protese ou sapato especial